Conventional chemotherapy for the treatment of cancers involves the critical problem of "acquired drug resistance" (i.e., the anti-cancer agent being administered becomes ineffective during treatment) and, particularly, the problem of "multidrug resistance" (i.e., acquired resistance to several kinds of anti-cancer agents). Specifically, solid cancer is generally resistant to anticancer agents. Disappearance of the activity of anticancer agents during therapy is widely experienced, and the mechanism underlying this phenomenon has been experimentally proven to be due to the acquisition of resistance of the cancer cells to anticancer agents. Currently, the acquisition of resistance is considered to be the greatest cause of failure of chemotherapy.
Among the aspects of acquired resistance, a phenomenon of biochemical interest is multiple drug resistance. This phenomenon has been seen in many cancer cells. For example, the table set forth below shows the degree of resistance of an adriamycin resistance cell line of human myeloma leukemia K562 to various anticancer agents.
______________________________________ Degree of resistance of adriamycin-resistant human myeloma leukemia cell line to various anticancer agents Drug Degree of resistance (fold) ______________________________________ Adriamycin 134 THP-adriamycin.sup.a) 42 Guanomycin 80 Aclacinomycin A 7.3 Mitomycin C 12 Actinomycin D 108 Mitozantron 80 Algomycin 26 AG-2 185 Menogarol 76 Vincristine 628 Vinblastine 122 Vindesin 841 Etoposide 44 Meitancin 74 Taxol &gt;3,800 ______________________________________ .sup.a) 4o-tetrahydropyranyl-adriamycin
Among the cytological changes related to the acquisition of resistance, the changes which can be easily analyzed biochemically are those induced by mutations. Many chemotherapeutic agents produce chromosomal aberrations (mutations) and induce resistance, as shown in the table below.
______________________________________ Chromosomal changes related to resistance induced by anticancer agents Drug Cancer Cell Chromosomal Change ______________________________________ 6-Mercaptopurine Human lymphocytes Structure and number 5-Fluorouracil Human colon Structure Cytosine arabinoside Leukemia Structure Methotrexate Human bone Structure and number marrow Mouse fetus Melphalan Human lymphocytes Structure Cyclophosphamide Human lymphocytes Structure and number Mouse cells Cisplatin Human lymphocytes Structure Actinomycin D Human lymphocytes Structure Daunomycin Human lymphocytes Structure and number Adriamycin Human lymphocytes Structure and number Mouse cells Bleomycin Human lymphocytes Structure Mouse cells Mitomycin C Human lymphocytes Mouse cells Vincristine Human lymphocytes Number Vinblastine Human lymphocytes Structure and number Hamster cells ______________________________________
Cancer cells that show multiple drug resistance have interesting characteristics, including 1) exhibiting resistance to other anticancer agents (cross-resistance), 2) promoting the excretion of the anticancer agent, and consequently, lowering the concentration of the anticancer agent in the cells, and 3) exhibiting changes in the membrane proteins.
For example, vinkaloid, colchicine and meitancin anticancer agents show cross-resistance to anthracyclin, and actinomycin agents which intercalate with DNA, and these drugs also show cross-resistance to the inhibitors of protein synthesis, puromycin and emetine. In the cells that show cross-resistance, the intracellular concentrations of colchicine, vincristine and vinblastine are kept low, often by the promotion of excretion, and partly by a change in the binding to the target, as shown in the table below.
______________________________________ Pharmacological action in the cells showing cross resistance to vincaalkaloid drugs Resistant Pharmacological Cell Drug action of drug ______________________________________ Colchicine-resistant Colchicine Decrease penetrability Chinese hamster Colchicine-resistant Colchicine Decrease in incorporation cell and retention, changes in binding Meitancin-resistant Colchicine Decreased incorporation, 3T3 lowered binding to surface Vincristine-resistant Vincristine Decrease in incorporation, P388 decreased retention Vincristine-resistant Vincristine Decreased incorporation Ehrlich due to accelerated excretion and decrease in retention Vincristine-resistant Vincristine Decreased incorporation, P388 accelerated excretion Vinblastine-resistant Vinblastine Decreased incorporation Ehrlich Vinblastine-resistant Vinblastine Decreased incorporation CEM and retention, changes in binding ______________________________________
As shown in the table above, the most peculiar characteristic of multiple drug resistance is the acceleration of membrane transport, especially the promotion of excretion.
Administration of larger quantities of an anti-cancer agent to prevent the decrease in the amount of agent in the tumor cells is not an effective remedy because side-effects are more severe.
To overcome this problem, calcium antagonists have been found to inhibit the accelerated extracellular excretion of anticancer agents by resistance cells. As a result, a large amount of the anticancer agents are accumulated in the resistance cells, resulting in the death of the cells. However, this method has the disadvantage that the effective amount of calcium antagonist exhibits an excessive hypotensive action and shows high toxicity.
Hence, there has been a demand for the development of new agents with higher therapeutic effect and lower toxicity.